Nanoparticulate compositions, which were first described in U.S. Pat. No. 5,145,684 ("the '684 Patent"), comprise a poorly soluble crystalline drug and a non-crosslinked surface stabilizer adsorbed to the surface of the drug. Nanoparticulate compositions are superior to macro-sized particulate drug formulations, as nanoparticulate drug formulations can exhibit reduced toxicity and enhanced efficacy (U.S. Pat. No. 5,399,363), enhanced bioavailability (U.S. Pat. No. 5,662,883), and enhanced stability (U.S. Pat. No. 5,665,331).
However, one of the problems that may be encountered with some nanoparticulate compositions is the solubilization and subsequent recrystallization of the component crystalline drug particles. This process results in large crystal formation over a period of time in the nanoparticulate composition. In addition, some nanoparticulate formulations exhibit particle aggregation over a period of time. Although such crystal growth and particle aggregation are often insignificant under normal conditions, under certain circumstances substantial crystal growth and particle aggregation can occur. This is observed with particular combinations of drugs and surface stabilizers, and even more so when the nanoparticulate composition is exposed to elevated temperatures for heat sterilization.
Crystal growth and particle aggregation in nanoparticulate preparations are highly undesirable for several reasons. Crystals in the nanoparticulate composition may cause increased toxic effects of the active ingredient, especially when the preparation is in an injectable formulation. This is also true for particle aggregation, as injectable formulations preferably have an effective average particle size of no greater than 250 nm.
In addition, for oral formulations, the presence of crystals and/or particle aggregation, and therefore varying particle sizes, creates a variable bioavailability profile because smaller particles dissolve faster than the larger aggregates or larger crystal particles. For drugs whose bioavailabiliy is dissolution-rate limited, a faster rate of dissolution is associated with greater bioavailability, and a slower rate of dissolution is associated with a lower bioavailability. This is because bioavailability is proportional to the surface area of an administered drug and, therefore, bioavailability increases with a reduction in the particle size of the dispersed agent (see U.S. Pat. No. 5,662,833). With a composition having widely varying particle sizes, bioavailability becomes highly variable and inconsistent and dosage determinations become difficult. Moreover, because such crystal growth and particle aggregation are uncontrollable and unpredictable, the quality of the nanoparticulate compositions is inconsistent. Finally, the mere occurrence of crystal growth indicates that the nanoparticulate formulation is not a "stable" pharmaceutical formulation, because such crystal growth indicates that the nanoparticulate drug particles are continually solubilizing and recrystallizing. This may in turn cause degradation of the active ingredient with numerous undesirable ramifications.
Two accepted methods (there are others, e.g. gamma irradiation) for sterilizing pharmaceutical products are heat sterilization and sterile filtration. Sterile filtration is an effective method for sterilizing solutions having a particle size of less than 0.22 microns (220 nm), because a 0.22 micron mesh size filter is sufficient to remove most bacteria. However, because nanoparticulate compositions have a size range, many of the particles of a typical nanoparticulate composition having an effective average particle size of 220 nm may have a size greater than 220 nm. and/or due to their shape, cannot be effectively sterilized by conventional filters. Such larger rigid crystal particles tend to clog the sterile filter. Thus, only nanoparticulate compositions having very small effective average particle sizes can be sterile filtered.
Sterile filtration is less desirable than conventional autoclaving (steam heat) at 121.degree. C. This is because with heat sterilization, the nanoparticulate composition is placed in the final storage container and sterilized (a single-step process). The product can then be marketed in the heat sterilized container. In contrast, the filter-sterilization step of sterile filtration is followed by a packaging step (a two-step process). The secondary packaging step of sterile filtration substantially increases the risk of contamination as compared to conventional autoclaving. For these reasons, the Food and Drug Administration generally requires submission of data demonstrating that a formulation cannot be autoclaved before approval of sterile filtration as a method of sterilization for a sterile product.
While crystal growth and particle aggregation in nanoparticulate compositions can occur over extended storage periods, such phenomena are more often observed after heat sterilization of the compositions. Aggregation of nanoparticle compositions upon heating is directly related to the precipitation of the surface stabilizer at temperatures above the cloud point of the surface stabilizer. At this point, the bound surface stabilizer molecules are likely to dissociate from the nanoparticles and precipitate, leaving the nanoparticles unprotected. The unprotected nanoparticles then aggregate into clusters of particles. Upon cooling, the surface stabilizer re-dissolves into the solution, which then coats the aggregated particles and prevents them from dissociating into smaller particles.
Several methods have been suggested in the prior art for preventing crystal growth and particle aggregation following heat sterilization, including adding a cloud point modifier or crystal growth modifier to the nanoparticulate composition and purifying the surface stabilizer. For example, U.S. Pat. No. 5,298,262 describes the use of an anionic or cationic cloud point modifier in nanoparticulate compositions and U.S. Pat. No. 5,346,702 describes nanoparticulate compositions having a nonionic surface stabilizer and a non-ionic cloud point modifier. The cloud point modifier enables heat sterilization of the nanoparticulate compositions with low resultant particle aggregation. U.S. Pat. No. 5,470,583 describes nanoparticulate compositions having a non-ionic surface stabilizer and a charged phospholipid as a cloud point modifier.
The prior art also describes methods of limiting crystal growth in a nanoparticulate composition by adding a crystal growth modifier (see U.S. Pat. Nos. 5,662,883 and 5,665,331). In addition, U.S. Pat. No. 5,302,401 describes nanoparticulate compositions having polyvinylpyrrolidone (PVP) as a surface stabilizer and sucrose as a cryoprotectant (allowing the nanoparticles to be lyophilized). The compositions exhibit minimal particle aggregation following lyophilization.
All of these various prior art methods share one common feature: they require an additional substance added to the nanoparticulate formulation to inhibit or prevent crystal growth and particle aggregation of the nanoparticulate composition. The addition of such a substance can be detrimental as it may induce adverse effects, particularly for injectable formulations. Moreover, cloud point and crystal growth modifiers are often highly toxic. Thus, this minimizes the usefulness of such substances in pharmaceutical compositions. In addition, the requirement of an additional substance to obtain a stable composition increases production costs.
Another method of limiting particle aggregation or crystal growth of nanoparticulate compositions during sterilization known prior to the present invention was the use of purified surface stabilizers. U.S. Pat. No. 5,352,459 describes nanoparticulate compositions having a purified surface stabilizer (having less than 15% impurities) and a cloud point modifier. Purification of surface stabilizers can be expensive and time consuming, thus significantly raising production costs of compositions requiring such stabilizers to produce a stable nanoparticulate composition.
There is a need in the art for nanoparticulate compositions of poorly soluble drugs that exhibit minimal particle aggregation and crystal growth, even following prolonged storage periods and/or exposure to elevated temperatures, and methods of making such compositions. The present invention satisfies these needs.